BRITISH MEDICAL JOURNAL
7 APRIL 1979
patients died within one week; in those to whom no cimetidine was given five patients died within a week. Of the treated group, 18 required no transfusion; of the untreated, 16. The volume of blood transfused to the treated group averaged 3-1 units, to the untreated 2 9 units.
955
a fit of pique a handful (probably about 60) of his mother's cimetidine tablets. When seen half an hour later he was drowsy but could be wakened; his respirations were slow and shallow but his pulse was strong and regular. His removal to the local hospital was arranged, but on removal to the ambulance he became so cyanosed and his breathing gave such cause for alarm that oxygen was administered during the journey to the hospital eight miles away. After gastric lavage his condition rapidly improved. In this case, respiratory depression as described in animal studies, presumably caused by the high dosage of cimetidine, caused for a while considerable anxiety. J B WILSON
Although no significant difference has been demonstrated between those patients treated with cimetidine and those without, we have not excluded the possibility that cimetidine may be of some value in the treatment of upper gastrointestinal bleeding: we think it likely that a much greater number of patients would need to be studied to demonstrate any benefit of cimetidine in such patients. S M Z A SIDDIQI G TILDESLEY Lockerbie, Dumfriesshire DGII IPD P T PICKENS R A McNAY General Hospital, Peripheral skin necrosis complicating Hartlepool TS24 9AH beta-blockade
Cimetidine and duodenal ulcer
used as an antineoplastic agent but it is of interest that it has a similar mode of action to that of the vinca alkaloids. Etoposide, although a derivative of podophyllum, does not inhibit microtubule polymerisation so a different mechanism of action must be sought for the reported neuropathy.3 Platinum diamminodichloride, which is soon to become commercially available (Neoplatin), is a drug of major interest because of its activity in several solid tumours. It may cause tinnitus and high-pitched frequency hearing loss,4 retrobulbar neuritis,5 and occasionally seizures6 7 (although these may be due to hyponatraemia). Bruckner et a17 reported three cases of peripheral neuropathy but did not elaborate on clinical presentation. We have observed a peripheral sensorimotor neuropathy of the lower limbs, with paraesthaesiae, loss of vibration sense, and absent ankle jerks in a 62-year-old patient with ovarian carcinoma after five courses of this drug. On withdrawal of chemotherapy the neuropathy resolved over two months. Neuropathy has not been reported with either of the other two drugs (adriamycin and cyclophosphamide) which were administered at the same time. Heavy metals can cause peripheral neuropathy. 8 Whether this is the mechanism of action of platinum diamminodichloride remains speculative. A M ARNOLD C J WILLIAMS
SIR,-I should like to add a further case of peripheral skin necrosis developing with betablockade to those recently reported by Dr R Gokal and others (17 March, p 722). A 57year-old man was treated for hypertension with atenolol 100 mg daily and Navidrex K. After 11 weeks of treatment, in February 1979, he complained of cold feet which were very tender to walk on. There was no previous history of peripheral vascular disease and all peripheral pulses were easily palpable. There were numerous areas of skin necrosis up to 1 cm diameter on the toes and heels. Atenolol CRC Medical Oncology Unit, was discontinued and the tenderness and Southampton General Hospital, coldness disappeared over the next seven to 10 Southampton S09 4XY days. No new lesions appeared after the 'Einhorn, L H, and Donohue, J, Annals of Internal Medicine, 1977, 87, 293. withdrawal of atenolol. C, et al, Cancer, 1975, 35, 1141. The pattern of the ischaemic lesions pro- 32 Falkson, Loike, J D, and Horwitz, S B, Biochemistry, 1976, 5435. 15, bably represents involvement of small vessels. Kovach, J S, et al, Cancer Chemotherapy Reports, In the patient described these lesions developed 1973, 57, 357. in the winter, as they did in the three cases 5 Ostrow, S, et al, Cancer Treatment Reports, 1978, 1591. 62, previously reported. The mechanism may be 6 Wiltshaw, E, and Kroner, T, Cancer Treatment 1976, 60, 55. Reports, potentiation of a-adrenoceptor activity,' as 7 H Bruckner, W, et al, Proceedings of the American suggested by Gokal et al. Increases in platelet Association for Cancer Research, 1977, 18, 339. counts have been described with metoprolol2 8 Bannister, R, (editor), Brain's Clinical Neurology, p 368. London, Oxford Medical Publications, 1978. but such increases have been small and unlikely to produce the necrotic lesions reported.
SIR,-In his second letter (17 March, p 755) Dr M Drury destroys his already feeble case for the use of cimetidine as a diagnostic agent. I do not see why, in the case of important upper abdominal pain, the "primary physician's diagnostic pathway is necessarily different from that of the hospital doctor." No competent physician refers all patients with upper abdominal pain for endoscopy or radiology; the first step is to make a clinical assessment. That assessment should pick out a small number of patients who are likely to have a duodenal ulcer, gastric ulcer, or gall stones. In these the diagnosis needs proper confirmation; the conditions are chronic and recurrent and it is unfair to the patient to treat him on the basis of provisional diagnosis alone. The response to cimetidine cannot be an adequate way of confirming or refuting these diagnoses. The remaining patients (who do not seem to have one of those three important diagnoses) certainly do not need cimetidine, and any response to that agent would be as meaningless as if they improved after drinking camphorated oil. The suggestion that cimetidine might help to differentiate oesophageal from cardiac pain P J REES is too ludicrous even to discuss. Science Laboratories, Cimetidine is already being prescribed Clinical Hospital, wastefully and extravagantly all over Britain. Guy's London SE1 9RT Doctors are failing to proceed in a rational, White, C de B, and Udwadia, B P, British J7ournal of diagnostic manner with regard to dyspepsia. Clinical Pharmacology, 1975, 2, 99. If they mistakenly believe there is some 2 Kutti, J, Bergstrom, A L, and Lundborg, P, New England Journal of Medicine, 1976, 295, 1079. economic advantage in trying this spurious "diagnostic test," let me remind them that the cost of a six-week course of cimetidine is approximately £28. The cost of an NHS Drug-induced peripheral neuropathies barium meal or upper gastrointestinal endoSIR,-The review by Dr Zohar Argov and scopy is likely to be considerably less. Professor Frank L Mastaglia (10 March, J R BENNETT p 663) on drug-induced peripheral neuropathies cites a comprehensive list of drugs Gastrointestinal Unit, which may cause this condition. There are, Hull Royal Infirmary, Hull HU3 2JZ however, some omissions in the list of antineoplastic agents which may not be apparent to those unfamiliar with these drugs. The authors quite rightly indicate that the Cimetidine overdosage mechanism of action of vincristine-induced SIR,-Since its introduction only a year or two neuropathy is due to its specific effect on ago cinietidine has been used so much in neurotubules (microtubules). Vinblastine may general practice that your article (17 February, also cause a sensorimotor and autonomic p 453) on the absence of toxicity in its use must neuropathy especially when used in high doses, as in current teratoma regimens.' have been of great interest to your readers. Podophyllum appears in the list when, in Three weeks later, a male patient aged 46, a chronic schizophrenic who was on tri- fact, the drug used in the study by Falkson fluoperazine, 2 mg twice daily, and hydroxy- et a12 was its semi-synthetic derivative zine hydrochloride, 25 mg twice daily, took in etoposide. Podophyllum is not currently
Vitamin C, disease, and surgical trauma SIR,-Your leading article "Vitamin C, disease, and surgical trauma" (17 February, p 437) refers to changes in leucocyte ascorbic acid (LAA) concentrations after surgery which were reported by Irvin et all in July 1978. They suggested that the fall in LAA concentrations was inversely related to the rise in white blood cell counts and concluded that the postoperative leucocytosis due to the surgical trauma and the release by the bone marrow of leucocytes with a low ascorbic acid content might partly account for the postoperative changes in LAA measurements. We have carried out similar studies in patients suffering from acute myocardial infarction.2 It is true that the apparent fall in the LAA concentration is associated with a rise in the white blood cell count, but the rise in the white blood cell count was due to a granulocytosis, presumably from mobilisation of the marginated pool of granulocytes. When, however, the ascorbic acid of granulocytes, lymphocytes, and platelets was measured separately in normal subjects the ascorbic acid content of the granulocyte was found to be about half that of the lymphocyte, and that of the platelet was somewhere between the two. We concluded, therefore, that the initial
7 APRIL 1979
patients died within one week; in those to whom no cimetidine was given five patients died within a week. Of the treated group, 18 required no transfusion; of the untreated, 16. The volume of blood transfused to the treated group averaged 3-1 units, to the untreated 2 9 units.
955
a fit of pique a handful (probably about 60) of his mother's cimetidine tablets. When seen half an hour later he was drowsy but could be wakened; his respirations were slow and shallow but his pulse was strong and regular. His removal to the local hospital was arranged, but on removal to the ambulance he became so cyanosed and his breathing gave such cause for alarm that oxygen was administered during the journey to the hospital eight miles away. After gastric lavage his condition rapidly improved. In this case, respiratory depression as described in animal studies, presumably caused by the high dosage of cimetidine, caused for a while considerable anxiety. J B WILSON
Although no significant difference has been demonstrated between those patients treated with cimetidine and those without, we have not excluded the possibility that cimetidine may be of some value in the treatment of upper gastrointestinal bleeding: we think it likely that a much greater number of patients would need to be studied to demonstrate any benefit of cimetidine in such patients. S M Z A SIDDIQI G TILDESLEY Lockerbie, Dumfriesshire DGII IPD P T PICKENS R A McNAY General Hospital, Peripheral skin necrosis complicating Hartlepool TS24 9AH beta-blockade
Cimetidine and duodenal ulcer
used as an antineoplastic agent but it is of interest that it has a similar mode of action to that of the vinca alkaloids. Etoposide, although a derivative of podophyllum, does not inhibit microtubule polymerisation so a different mechanism of action must be sought for the reported neuropathy.3 Platinum diamminodichloride, which is soon to become commercially available (Neoplatin), is a drug of major interest because of its activity in several solid tumours. It may cause tinnitus and high-pitched frequency hearing loss,4 retrobulbar neuritis,5 and occasionally seizures6 7 (although these may be due to hyponatraemia). Bruckner et a17 reported three cases of peripheral neuropathy but did not elaborate on clinical presentation. We have observed a peripheral sensorimotor neuropathy of the lower limbs, with paraesthaesiae, loss of vibration sense, and absent ankle jerks in a 62-year-old patient with ovarian carcinoma after five courses of this drug. On withdrawal of chemotherapy the neuropathy resolved over two months. Neuropathy has not been reported with either of the other two drugs (adriamycin and cyclophosphamide) which were administered at the same time. Heavy metals can cause peripheral neuropathy. 8 Whether this is the mechanism of action of platinum diamminodichloride remains speculative. A M ARNOLD C J WILLIAMS
SIR,-I should like to add a further case of peripheral skin necrosis developing with betablockade to those recently reported by Dr R Gokal and others (17 March, p 722). A 57year-old man was treated for hypertension with atenolol 100 mg daily and Navidrex K. After 11 weeks of treatment, in February 1979, he complained of cold feet which were very tender to walk on. There was no previous history of peripheral vascular disease and all peripheral pulses were easily palpable. There were numerous areas of skin necrosis up to 1 cm diameter on the toes and heels. Atenolol CRC Medical Oncology Unit, was discontinued and the tenderness and Southampton General Hospital, coldness disappeared over the next seven to 10 Southampton S09 4XY days. No new lesions appeared after the 'Einhorn, L H, and Donohue, J, Annals of Internal Medicine, 1977, 87, 293. withdrawal of atenolol. C, et al, Cancer, 1975, 35, 1141. The pattern of the ischaemic lesions pro- 32 Falkson, Loike, J D, and Horwitz, S B, Biochemistry, 1976, 5435. 15, bably represents involvement of small vessels. Kovach, J S, et al, Cancer Chemotherapy Reports, In the patient described these lesions developed 1973, 57, 357. in the winter, as they did in the three cases 5 Ostrow, S, et al, Cancer Treatment Reports, 1978, 1591. 62, previously reported. The mechanism may be 6 Wiltshaw, E, and Kroner, T, Cancer Treatment 1976, 60, 55. Reports, potentiation of a-adrenoceptor activity,' as 7 H Bruckner, W, et al, Proceedings of the American suggested by Gokal et al. Increases in platelet Association for Cancer Research, 1977, 18, 339. counts have been described with metoprolol2 8 Bannister, R, (editor), Brain's Clinical Neurology, p 368. London, Oxford Medical Publications, 1978. but such increases have been small and unlikely to produce the necrotic lesions reported.
SIR,-In his second letter (17 March, p 755) Dr M Drury destroys his already feeble case for the use of cimetidine as a diagnostic agent. I do not see why, in the case of important upper abdominal pain, the "primary physician's diagnostic pathway is necessarily different from that of the hospital doctor." No competent physician refers all patients with upper abdominal pain for endoscopy or radiology; the first step is to make a clinical assessment. That assessment should pick out a small number of patients who are likely to have a duodenal ulcer, gastric ulcer, or gall stones. In these the diagnosis needs proper confirmation; the conditions are chronic and recurrent and it is unfair to the patient to treat him on the basis of provisional diagnosis alone. The response to cimetidine cannot be an adequate way of confirming or refuting these diagnoses. The remaining patients (who do not seem to have one of those three important diagnoses) certainly do not need cimetidine, and any response to that agent would be as meaningless as if they improved after drinking camphorated oil. The suggestion that cimetidine might help to differentiate oesophageal from cardiac pain P J REES is too ludicrous even to discuss. Science Laboratories, Cimetidine is already being prescribed Clinical Hospital, wastefully and extravagantly all over Britain. Guy's London SE1 9RT Doctors are failing to proceed in a rational, White, C de B, and Udwadia, B P, British J7ournal of diagnostic manner with regard to dyspepsia. Clinical Pharmacology, 1975, 2, 99. If they mistakenly believe there is some 2 Kutti, J, Bergstrom, A L, and Lundborg, P, New England Journal of Medicine, 1976, 295, 1079. economic advantage in trying this spurious "diagnostic test," let me remind them that the cost of a six-week course of cimetidine is approximately £28. The cost of an NHS Drug-induced peripheral neuropathies barium meal or upper gastrointestinal endoSIR,-The review by Dr Zohar Argov and scopy is likely to be considerably less. Professor Frank L Mastaglia (10 March, J R BENNETT p 663) on drug-induced peripheral neuropathies cites a comprehensive list of drugs Gastrointestinal Unit, which may cause this condition. There are, Hull Royal Infirmary, Hull HU3 2JZ however, some omissions in the list of antineoplastic agents which may not be apparent to those unfamiliar with these drugs. The authors quite rightly indicate that the Cimetidine overdosage mechanism of action of vincristine-induced SIR,-Since its introduction only a year or two neuropathy is due to its specific effect on ago cinietidine has been used so much in neurotubules (microtubules). Vinblastine may general practice that your article (17 February, also cause a sensorimotor and autonomic p 453) on the absence of toxicity in its use must neuropathy especially when used in high doses, as in current teratoma regimens.' have been of great interest to your readers. Podophyllum appears in the list when, in Three weeks later, a male patient aged 46, a chronic schizophrenic who was on tri- fact, the drug used in the study by Falkson fluoperazine, 2 mg twice daily, and hydroxy- et a12 was its semi-synthetic derivative zine hydrochloride, 25 mg twice daily, took in etoposide. Podophyllum is not currently
Vitamin C, disease, and surgical trauma SIR,-Your leading article "Vitamin C, disease, and surgical trauma" (17 February, p 437) refers to changes in leucocyte ascorbic acid (LAA) concentrations after surgery which were reported by Irvin et all in July 1978. They suggested that the fall in LAA concentrations was inversely related to the rise in white blood cell counts and concluded that the postoperative leucocytosis due to the surgical trauma and the release by the bone marrow of leucocytes with a low ascorbic acid content might partly account for the postoperative changes in LAA measurements. We have carried out similar studies in patients suffering from acute myocardial infarction.2 It is true that the apparent fall in the LAA concentration is associated with a rise in the white blood cell count, but the rise in the white blood cell count was due to a granulocytosis, presumably from mobilisation of the marginated pool of granulocytes. When, however, the ascorbic acid of granulocytes, lymphocytes, and platelets was measured separately in normal subjects the ascorbic acid content of the granulocyte was found to be about half that of the lymphocyte, and that of the platelet was somewhere between the two. We concluded, therefore, that the initial
